Chromosome banding techniques have facilitated the identification of specific human chromosomes and presently provide the major basis upon which chromosomal aberrations are diagnosed. The interpretation of chromosome banding patterns requires skilled personnel and is often technically difficult, especially with respect to detecting minor structural changes and when analyzing complex karyotypes, such as those of highly aneuploid tumor cells. An additional complexity is that readable metaphase chromosome spreads are sometimes very difficult or impossible to prepare from certain cell types or tissues. Alternative methods for identifying chromosomal aberrations would be valuable because they could augment current methods of cytogenic analysis, particularly if such alternative methods were applicable to both mitotic and interphase cell populations.
Over the past few years, a considerable body of evidence has been obtained which indicates that the DNA of individual chromosomes occupy focal territories, or spatially cohesive domains, within mammalian interphase nuclei. Cremer, T. et al., Hum. Genet., 60:46-56 (1982); Hens, L. et al., Exp. Cell Res., 149:257-269 (1983); Schardin, M. et al., Hum. Genet., 71:281-287 (1985); Manuelidis, L., Hum Genet., 71:288-293 (1985); and Pinkel, D. et al., Proc. Natl. Acad. Sci. USA, 83:2934-2938 (1986). These observations suggest that chromosome-specific probe sets could be used to detect numerical or structural aberrations of chromosomal domains in non-mitotic cells, an approach termed "interphase cytogenics". Cremer, T. et al., Hum. Genet., 74:346-352 (1986). Indeed, recent in situ hybridization studies have demonstrated the prenatal diagnosis of trisomy-18 with interphase cells and the detection of numerical chromosomal abnormalities in tumor cells lines using chromosome-specific repetitive DNAs as probes. Cremer, T. et al., Hum. Genet., 74:346-352 (1986) and Cremer, T. et al., Exp. Cell Res., 176:119-220 (1988). All chromosome-specific repetitive DNAs reported to date are localized to discrete subregions of each chromosome and, thus, such DNA probes are unsuitable for analyses of many types of chromosomal aberrations (e.g., translocations and deletions). If it were possible to detect uniquely the spectrum of sequences comprising a specific chromosome, analysis of aberrations of chromosomal domains in non-mitotic cells would be possible. Furthermore, such a general labeling technique would make it possible to address fundamental questions concerning the spatial organization of chromosomal DNA within interphase nuclei.